Curr Diab Rep (2015) 15:12 DOI 10.1007/s11892-015-0578-5
OTHER FORMS OF DIABETES (R BONADONNA, SECTION EDITOR)
Lipodystrophic Diabetes Mellitus: a Lesson for Other Forms of Diabetes? Romina Ficarella & Luigi Laviola & Francesco Giorgino
# Springer Science+Business Media New York 2015
Abstract Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes.
Keywords Lipodystrophy . Adipose tissue . Diabetes mellitus . Insulin resistance . Adipogenesis
This article is part of the Topical Collection on Other Forms of Diabetes R. Ficarella : L. Laviola : F. Giorgino (*) Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Giulio Cesare, n. 11, 70124 Bari, Italy e-mail: [email protected] R. Ficarella e-mail: [email protected] L. Laviola e-mail: [email protected]
Introduction Lipodystrophies include a heterogeneous group of disorders characterized by loss of adipose tissue (AT) in the subcutaneous compartment and several metabolic abnormalities associated with insulin resistance [1]. Although the definition of lipodystrophy is a Bwork in progress,^ as suggested by Rother and Brown [2••], the conventional classification of lipodystrophy, based on the topography of fat loss (general or partial) and on the inheritance (congenital or acquired), identifies four different subtypes: congenital generalized lipodystrophy, acquired generalized lipodystrophy, familial partial lipodystrophy (FPL), and acquired partial lipodystrophy (APL). In addition to the main characteristics of fat loss, these disorders are frequently characterized by hypertriglyceridemia, steatohepatitis, acanthosis nigricans, ovarian hyperandrogenism, and type 2 diabetes mellitus [1]. Multiple metabolic abnormalities, including insulin resistance, increased levels of free fatty acids and triglycerides, ectopic fat in skeletal muscle and hepatocytes, and abnormal secretion of adipokines, are typically observed in lipodystrophic patients but are also common in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) [3]. It is interesting to note that the consequences of lipoatrophy are remarkably similar to those of excessive fat accumulation, as observed in human obesity [4••]. Indeed, alterations in AT development and/or function due to mutations in genes involved in adipogenesis, lipid storage within the fat cell, or lipid droplet formation and turnover may cause severe metabolic consequences [5]. Even though the loss of fat per se may represent the primary cause of these metabolic changes, mitochondrial dysfunction [6], enhanced oxidative stress, and inflammation have been shown to contribute to the pathophysiology of the lipodystrophic phenotypes. In this review, we describe the Bmetabolic lipodystrophies^ as a disease model shedding light on specific pathophysiological
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mechanisms that can be informative for better understanding of more common metabolic diseases in humans, including visceral obesity, MS, and T2DM, potentially highlighting the basis for novel-integrated clinical approaches and therapies.
Classification of Lipodystrophies Lipodystrophies are generally diagnosed on the basis of the topography of fat loss (general or partial) and on the potential inheritance (congenital or acquired). Therefore, congenital generalized lipodystrophy (CGL), acquired generalized lipodystrophy (AGL), FPL, and APL represent the four main groups of disorders [1]. Patients with AGL—also designed as Lawrence syndrome and typically associated with autoantibodies against AT and other autoimmune diseases [7, 8]—develop progressive fat loss beginning in childhood or adolescence, with the initial involvement of the face and upper extremities. APL or Barraquer-Simons syndrome, of unknown etiology, is characterized by a gradual loss of subcutaneous fat progressing in a cephalocaudal direction with variable lower limit, with or without increased fat accumulation in the lower body [9]. A relatively frequent form of acquired lipodystrophy is induced by a highly active antiretroviral treatment (HAART) in HIV subjects, in which a severe lipoatrophy of subcutaneous AT associated with abdominal fat accumulation, severe dyslipidemia, insulin resistance, impaired glucose tolerance, and type 2 diabetes occur [10, 11]. Two main types of antiretroviral drugs are involved: nucleoside reverse transcriptase inhibitor (NRTI) analogues, which inhibit mitochondrial DNA polymerase-γ, the enzyme necessary for the replication of mitochondrial DNA [12] thereby inducing mitochondrial dysfunction, and HIV protease inhibitors (PIs). Some PIs also inhibit ZMPSTE24, the enzyme responsible for the removal of the farnesylated tail of prelamin A, leading to precursor accumulation inside the cells and impaired organization of the nuclear membrane [13], as also occurs in homozygous mutations in the gene encoding the ZMPSTE24 (as reported below). CGL, named Berardinelli-Seip congenital lipodystrophy (BSCL), is characterized by severe insulin resistance and the complete absence of AT starting from birth or early infancy. Mutations in proteins involved in adipocyte differentiation (seipin, BSCL2/BSCL2 [14]), FA uptake by adipocytes (caveolin-1, CAV1/BSCL3 [15]; DNA polymerase I and transcript release factor, PTRF/BSCL4 [16]), or triglyceride synthesis (1-acylglycerol-3-phosphate-O-acyltransferase 2, AGPAT2/ BSCL1 [17]) lead to a generalized lack of AT [18]. Mutations in other genes have been associated with generalized lipodystrophy: heterozygous mutations of LMNA, the gene encoding for A-type lamins, and homozygous mutations
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in the gene encoding the ZMPSTE24 (zinc metalloproteinase STE24 homolog) protease, which cleaves prelamin A into mature lamin A [1]. These two genes are respectively causative of the Hutchinson-Gilford progeria [19] and other progeroid syndromes [20], such as type B mandibuloacral dysplasia (MAD) [21, 18]. In FPLs, the clinical phenotype appears after puberty and the causative genes are peroxisome proliferator-activated receptor gamma (PPARγ) [22] and lamin A/C [23], encoding for nuclear proteins, or genes involved in insulin signaling, such as Akt2 [24], or regulators of the formation, trafficking, or maintenance of lipid droplets, including CIDEC [25] and perilipin [26]. Impaired AT Development and Function and Lipodystrophies In the last 15 years, novel mutations have been found to be responsible for lipodystrophic syndromes, bearing new light on the relationship between AT function and glucose and lipid metabolism [4••]. The lipodystrophy-causing genes include PPARγ, a key transcription factor for adipocyte differentiation; perilipin, involved in the regulation of lipolysis at the lipid droplet (LD) site; CIDEC, involved in the regulation of LD structure; the serine-threonine kinase Akt2; AGPAT2, which participates to triglyceride and glycerophospholipid synthesis; seipin, involved in LD formation; and caveolin-1, a structural protein of caveolae and LD. All of these genes are critical for the maturation of preadipocytes and/or the maintenance of the mature adipocyte phenotype, enlightening the leading role of AT for global metabolic homeostasis [4••]. Experimental mouse models, such as A-ZIP/F-1 fatless mice [27] and Agpat2-null lipodystrophic mice [28], show impaired glucose metabolism and insulin resistance. Moreover, after transplantation of normal subcutaneous AT into A-ZIP/F-1 fatless mice, the ectopic fat deposition was found to be reduced, with an improvement of insulin-mediated glucose uptake [27]. These results support the hypothesis that impaired AT development and/or function may result in metabolic abnormalities, which are commonly observed in T2DM and MS. The genetic lipodystrophies may thus serve as a model of the essential role of AT in the regulation of glucose and energy homeostasis. The contribution of relevant genes controlling AT differentiation and insulin signaling in the pathogenesis of human lipodystrophies has been widely addressed in recent focused reviews [4••, 18, 29–31]. More recently, other genetic lipodystrophies have been described, due to mutations which underline novel key steps in AT development and function, as outlined below. c-fos Knebel et al. reported a de novo homozygous point mutation (c.–439, T→A) in the c-fos promoter in a patient with CGL and insulin resistance. Fibroblasts isolated from the
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patient revealed a reduction of basal and inducible c-fos transcriptional activity, essential to initiate adipocyte differentiation, likely resulting in CGL [32]. p85α Chudasama et al. revealed a new element of the complex mechanism leading to partial lipodystrophy by identifying the regulatory subunit of PI3K, p85α, which is encoded by PIK3R1, as a genetic cause of the SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Rieger anomaly, and teething delay), also displaying partial lipodystrophy. PIK3R1 is a central component of the PI3K signaling pathway regulating cell metabolism and proliferation. Using a whole-exome sequencing approach, the authors identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two distinct families with partial lipodystrophy. This mutation prevents the association of p85α with IRS-1 and thus results in reduced Akt activation and insulin signaling in fibroblasts from the affected individuals [33], providing a link between the impaired insulin signaling and development of altered adipogenesis and the lipodystrophy syndrome. Phosphate Cytidylyltransferase 1 Alpha Payne et al. identified two unrelated patients with biallelic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in the Kennedy pathway of phospholipid biosynthesis [34]. The mutations result in a marked reduction in PCYT1A expression and in the synthesis of phosphatidylcholine, the major glycerophospholipid in eukaryotic cells and an essential component in all cellular membranes. The clinical phenotype includes lipodystrophy, severe fatty liver, low HDL cholesterol levels, marked insulin resistance, and diabetes, providing evidence for an essential role for PCYT1A-generated phosphatidylcholine in insulin action and in the regulation of white AT physiology [35]. Additionally, the pathophysiology of this specific lipodystrophy suggests that plasma membrane flexibility, determined by phospholipid composition, is important for the trafficking of both insulin-independent and insulindependent glucose transporters (GLUTs) and the effectiveness of glucose transport [36], providing an additional common pathogenic mechanism between lipodystrophy and impaired glucose metabolism. WRN (DNA helicase) Donadille et al. reported the cases of two women investigated for partial lipodystrophy (predominant fat accumulation in the trunk and reduced AT in the lower limbs) and severe insulin resistance, which revealed Werner’s syndrome due to homozygous or compound heterozygous, non-sense or frameshift mutations in the WRN gene, encoding a RecQ DNA helicase/ exonuclease involved in DNA replication and repair [37]. Bearing in mind that high glucose levels have been
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shown to induce oxidative DNA damage in diabetes, DNA replication and/or repair can be considered as a key metabolic target, potentially involved in the pathogenesis of more common metabolic diseases. Moreover, the role of insulin and glucose in modulating the expression of the DNA repair machinery is well established [38], supporting the hypothesis that impaired insulin action may be associated with deficient DNA repair function. Relevant to this concept, lymphocytes from diabetic patients displayed higher susceptibility to DNA damage when exposed to hydrogen peroxide or doxorubicin as well as decreased efficiency in repairing DNA injury [39]. Mandibular Hypoplasia, Deafness, and Progeroid Syndrome Progressive loss of subcutaneous AT, with concomitant severe insulin resistance, is a major feature of the recently described mandibular hypoplasia, deafness, and progeroid (MDP) syndrome [40]. The most prominent phenotype is the lack of subcutaneous AT which is first noted in early childhood, in contrast with the marked increase in visceral AT, and the clinical and biochemical evidence of insulin resistance despite BMI values G) in exon 9 of LMNA gene [76]. Thiazolidinediones The PPARγ agonist TZDs are potent insulin sensitizers that activate PPARγ, the master regulator of adipocyte differentiation, resulting in enhanced adipogenesis and adiponectin production, enhanced insulin secretion, and improved glucose tolerance [77], thus representing optimal candidates for AT dysfunction and diabetes in lipodystrophic patients. TZDs have been shown to increase subcutaneous fat in patients with lipodystrophy [78] and HIV-associated lipodystrophy [79, 80], by promoting adipocyte differentiation from AT progenitor cells. Specifically, therapy with pioglitazone has been shown to address multiple metabolic abnormalities associated with lipodystrophy, including increased adiponectin, improved lipid profiles and endothelial function, and amelioration of insulin resistance [81]. Fibroblast Growth Factor 21 Fibroblast growth factor 21 (FGF21), a circulating hepatokine, is also able to regulate the activity of PPARγ. Moreover, FGF21-knockout (KO) mice present with mild lipodystrophy, defects in PPARγ signaling, decreased body fat, and attenuation of PPARγdependent gene expression and are refractory to the beneficial
insulin-sensitizing effects of the PPARγ agonist rosiglitazone [82]. Adding recombinant FGF21 in the differentiation medium of preadipocytes derived from FGF21-KO mice resulted in effective restoration of gene expression of PPARγ, FA binding protein (aP2), and FA synthase (Fasn) and of lipid accumulation [82]. Although additional studies will be required to determine the relevance of FGF21 expression in human white AT in both physiologic and pharmacological contexts, these results suggest that FGF21 may contribute to the antidiabetic response to TZDs through PPARγ-dependent mechanisms, by increasing the number of small, metabolically active adipocytes and by raising circulating adiponectin levels [82]. LY2405319, a variant of FGF21, was recently tested in a randomized, placebo-controlled, double-blind proof-ofconcept trial in patients with obesity and T2DM. LY2405319 treatment resulted in significant improvements in dyslipidemia, body weight, fasting insulin, and adiponectin levels, suggesting that FGF21-based therapies may be effective for the treatment of selected metabolic disorders [83].
Conclusions Lipodystrophies are rare diseases, in which various degrees of AT loss are associated with severe lipid and glucose abnormalities, resulting into impairments of glucose tolerance or overt diabetes with a negative impact on the cardiovascular system and hepatic metabolism leading to related complications. The genetic bases of human lipodystrophies have been recently deciphered, highlighting the functional role of new proteins. Clinical whole-exome sequencing and murine models studies have greatly contributed to dissect the genetic complexities of lipodystrophies and their related metabolic
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features, largely shared by more common forms of diabetes. Most of the proteins or functions affected by mutations or antiretroviral therapies result in impaired adipogenesis and fat distribution as well as in reduced insulin sensitivity, triglyceride storage, and formation of the lipid droplet in adipocytes, revealing novel aspects of AT biology with potential impact on both diabetes research and the definition of novel treatments and/or prevention strategies. Villarroya et al. in 2007 [84] already described lipodystrophies as a lesson for obesity, emphasizing a common pathogenesis between these two metabolic disorders (Fig. 1). If we consider the AT expandability/ lipotoxicity hypothesis as the Bcommon soil^ for lipodystrophies and T2DM, understanding the pathogenesis and treatment of lipodystrophies may help to better address the abnormalities in lipid metabolism and adipocyte function underlying more common forms of diabetes.
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Conflict of Interest Romina Ficarella, Luigi Laviola, and Francesco Giorgino declare that they have no conflict of interest. 10. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. 11.
References 12.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Strickland LR, Guo F, Lok K, Garvey WT. Type 2 diabetes with partial lipodystrophy of the limbs: a new lipodystrophy phenotype. Diabetes Care [Internet]. 2013 [cited 2014 Mar 26];36:2247–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23423695. 2.•• Rother KI, Brown RJ. Novel forms of lipodystrophy: why should we care? Diabetes Care [Internet]. 2013 [cited 2014 Mar 26];36: 2142–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 23881965. This commentary highlights the heterogeneity of lipodystrophies, focusing on the need for a better nosographic definition, the relationship with fat accumulation and obesity, the metabolic impact, and the therapeutic approaches involving the use of leptin. 3. Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature [Internet]. 2006 [cited 2014 Mar 19];444:881–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167477. 4.•• Vatier C, Bidault G, Briand N, Guénantin A-C, Teyssières L, Lascols O, et al. What the genetics of lipodystrophy can teach us about insulin resistance and diabetes. Curr. Diab. Rep. [Internet]. 2013 [cited 2014 Mar 26];13:757–67. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24026869. This review article describes the genetics of lipodystrophic syndromes and addresses the mechanisms by which impaired adipogenesis and adipocyte lipid storage result in systemic metabolic and endocrine abnormalities.
13.
1.
14.
15.
16.
17.
18.
Araújo-Vilar D, Lattanzi G, González-Méndez B, Costa-Freitas AT, Prieto D, Columbaro M, et al. Site-dependent differences in both prelamin A and adipogenic genes in subcutaneous adipose tissue of patients with type 2 familial partial lipodystrophy. J. Med. Genet. [Internet]. 2009 [cited 2014 Mar 27];46:40–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18805829. Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, et al. Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy. J. Clin. Endocrinol. Metab. [Internet]. 2012 [cited 2014 Mar 26];97:E438–42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3380089&tool=pmcentrez&rendertype=abstract. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). [Internet]. 2003 [cited 2014 Mar 26];82:129–46. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/12640189. Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, et al. Complement abnormalities in acquired lipodystrophy revisited. J. Clin. Endocrinol. Metab. [Internet]. 2009 [cited 2014 Jun 23];94:10–6. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18854390. Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. [Internet]. 2011 [cited 2014 Mar 20];96:3313–25. Available from: http://www.ncbi. nlm.nih.gov/pubmed/21865368. Villarroya F, Domingo P, Giralt M. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Trends Pharmacol. Sci. [Internet]. 2005 [cited 2014 Apr 3];26:88–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15681026. Kalra S, Agrawal N. Diabetes and HIV: current understanding and future perspectives. Curr. Diab. Rep. [Internet]. 2013 [cited 2014 Mar 26];13:419–27. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/23446780. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion [Internet]. 2004 [cited 2014 Oct 21];4:111–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16120376. Goulbourne CN, Vaux DJ. HIV protease inhibitors inhibit FACE1/ ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy? Biochem. Soc. Trans. [Internet]. 2010 [cited 2014 Oct 21];38:292–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20074077. Magré J, Delépine M, Khallouf E, Gedde-Dahl T, Van Maldergem L, Sobel E, et al. Identification of the gene altered in BerardinelliSeip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28:365–70. Kim CA, Delépine M, Boutet E, El Mourabit H, Le Lay S, Meier M, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93:1129–34. Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009:2623–33. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31: 21–3. Vigouroux C, Caron-Debarle M, Le Dour C, Magré J, Capeau J. Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Int. J. Biochem. Cell Biol. [Internet]. 2011 [cited 2014 Jun 10];43:862–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21392585.
12 19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29. 30.
31.
32.
33.
34.
Page 8 of 10 Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–8. Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D’Apice MR, et al. Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab. 2009;94:4971–83. Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12:1995–2001. Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, et al. Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3. ST – Dominant negative mutations in human. Available from: :// 000084482000034. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109–12. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8. Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 2009;1:280–7. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N. Engl. J. Med. [Internet]. 2011 [cited 2014 Mar 21];364:740–8. Available from: http://www.pubmedcentral.nih. g o v / a r t i c l e r e n d e r. f c g i ? a r t i d = 3 7 7 3 9 1 6 & t o o l = pmcentrez&rendertype=abstract. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J. Biol. Chem. [Internet]. 2000 [cited 2014 Jun 11];275:8456–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10722680. Agarwal AK, Sukumaran S, Cortés VA, Tunison K, Mizrachi D, Sankella S, et al. Human 1-acylglycerol-3-phosphate Oacyltransferase isoforms 1 and 2: biochemical characterization and inability to rescue hepatic steatosis in Agpat2(−/−) gene lipodystrophic mice. J. Biol. Chem. [Internet]. 2011 [cited 2014 Ju n 11 ] ; 28 6: 37 676 –9 1. Avai l a b l e fr o m : http:/ /www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3199511&tool= pmcentrez&rendertype=abstract. Jeninga EH, Kalkhoven E. Central players in inherited lipodystrophies. Trends Endocrinol Metab. 2010;21:581–8. Rochford JJ. Molecular mechanisms controlling human adipose tissue development: insights from monogenic lipodystrophies. Expert Rev Mol Med. 2010;12:e24. Huang-Doran I, Sleigh A, Rochford JJ, O’Rahilly S, Savage DB. Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol. 2010;207:245–55. Knebel B, Kotzka J, Lehr S, Hartwig S, Avci H, Jacob S, et al. A mutation in the c-fos gene associated with congenital generalized lipodystrophy. Orphanet J. Rare Dis. [Internet]. 2013 [cited 2014 Jun 11];8:119. Available from: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3750569&tool=pmcentrez&rendertype= abstract. Chudasama KK, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, et al. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am. J. Hum. Genet. [Internet]. 2013 [cited 2014 Mar 26];93:150–7. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3710758&tool=pmcentrez&rendertype=abstract. Gibellini F, Smith TK. The Kennedy pathway—de novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB
Curr Diab Rep (2015) 15:12 Life [Internet]. 2010 [cited 2014 Jul 21];62:414–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20503434. 35. Payne F, Lim K, Girousse A, Brown RJ, Kory N, Robbins A, et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc. Natl. Acad. Sci. [Internet]. 2014 [cited 2014 Jun 4]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24889630. 36. Weijers RNM. Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus. Curr. Diabetes Rev. [Internet]. 2012 [cited 2014 May 30];8:390–400. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3474953&tool=pmcentrez&rendertype=abstract. 37. Donadille B, D’Anella P, Auclair M, Uhrhammer N, Sorel M, Grigorescu R, et al. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet J. Rare Dis. [Internet]. 2013 [cited 2014 Jun 11];8:106. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3720184&tool=pmcentrez&rendertype=abstract. 38. Merkel P, Khoury N, Bertolotto C, Perfetti R. Insulin and glucose regulate the expression of the DNA repair enzyme XPD. Mol Cell Endocrinol. 2003;201:75–85. Available from: http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt= Citation&list_uids=12706296. 39. Blasiak J, Arabski M, Krupa R, Wozniak K, Zadrozny M, Kasznicki J, et al. DNA damage and repair in type 2 diabetes mellitus. Mutat Res. 2004;554:297–304. 40. Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, et al. A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism. J Clin Endocrinol Metab. 2010; E192–E197. 41. Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat. Genet. [Internet]. 2013 [cited 2014 Jun 11];45:947–50. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3785143&tool=pmcentrez&rendertype=abstract. 42. Miranda DA, Kim J-H, Nguyen LN, Cheng W, Tan BC, Goh VJ, et al. Fat storage-inducing transmembrane protein 2 is required for normal fat storage in adipose tissue. J. Biol. Chem. [Internet]. 2014 [cited 2014 May 28];289:9560–72. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24519944. 43. Frontini A, Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 2010;253–6. 44. Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature. 2014;510:76–83. Available from: http://www.ncbi.nlm. nih.gov/pubmed/24899307 45. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–5. 46. Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–76. 47. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24100998. 48. Guerra C, Navarro P, Valverde AM, Arribas M, Brüning J, Kozak LP, et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest. 2001;108:1205–13. 49. Van de Woestijne AP, Monajemi H, Kalkhoven E, Visseren FLJ. Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management. Obes. Rev. [Internet]. 2011 [cited 2014 Jun 25];12:829–40. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/21749607.
Curr Diab Rep (2015) 15:12 50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes [Internet]. 2003 [cited 2014 Jun 25];52:2461–74. Available from: http://www.ncbi. nlm.nih.gov/pubmed/14514628. Borén J, Taskinen M-R, Olofsson S-O, Levin M. Ectopic lipid storage and insulin resistance: a harmful relationship. J. Intern. Med. [Internet]. 2013 [cited 2014 Jun 20];274:25–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23551521. Giralt M, Díaz-Delfín J, Gallego-Escuredo JM, Villarroya J, Domingo P, Villarroya F. Lipotoxicity on the basis of metabolic syndrome and lipodystrophy in HIV-1-infected patients under antiretroviral treatment. Curr. Pharm. Des. [Internet]. 2010 [cited 2014 Jun 12];16:3371–8. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/20687888. Vigouroux C, Maachi M, Nguyên T-H, Coussieu C, Gharakhanian S, Funahashi T, et al. Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS. 2003;17:1503–11. Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. Int. J. Obes. (Lond). [Internet]. 2010 [cited 2014 Jun 9];34:949–59. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20065965. Patti M-E, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. [Internet]. 2010 [cited 2014 Mar 31];31: 364–95. Available from: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3365846&tool=pmcentrez&rendertype= abstract. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. [Internet]. 2008 [cited 2014 Mar 31];7:45–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18177724. Villarroya J, Giralt M, Villarroya F. Mitochondrial DNA: an upand-coming actor in white adipose tissue pathophysiology. Obesity (Silver Spring). [Internet]. 2009 [cited 2014 Mar 21];17: 1814–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 19461585. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol. Cell. Biol. [Internet]. 2003 [cited 2014 Apr 1];23:1085–94. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=140688&tool=pmcentrez&rendertype=abstract. Koh EH, Park J-Y, Park H-S, Jeon MJ, Ryu JW, Kim M, et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes [Internet]. 2007 [cited 2014 Apr 3];56: 2973–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17827403. Shi X, Burkart A, Nicoloro SM, Czech MP, Straubhaar J, Corvera S. Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells. J. Biol. Chem. [Internet]. 2008 [cited 2014 Mar 27];283:30658–67. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2576555&tool=pmcentrez&rendertype=abstract. Domingo P, Gutierrez MDM, Gallego-Escuredo JM, Torres F, Mateo GM, Villarroya J, et al. Effects of switching from stavudine to raltegravir on subcutaneous adipose tissue in HIV-infected patients with HIV/HAART-associated lipodystrophy syndrome (HALS). A clinical and molecular study. PLoS One [Internet]. 2014 [cited 2014 Mar 26];9:e89088. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3935839&tool= pmcentrez&rendertype=abstract. Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, et al. Cardiovascular pathology in Hutchinson-Gilford progeria:
Page 9 of 10 12
63.
64.
65.
66.•
67.
68.
69.
70.
71.
72.
73.
74.
correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol. 2010;30:2301–9. Bidault G, Garcia M, Vantyghem M-C, Ducluzeau P-H, Morichon R, Thiyagarajah K, et al. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler. Thromb. Vasc. Biol. [Internet]. 2013 [cited 2014 Mar 26];33:2162–71. Available from: http://www.ncbi. nlm.nih.gov/pubmed/23846499. Bays HE, Toth PP, Kris-Etherton PM, Abate N, Aronne LJ, Brown WV, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J. Clin. Lipidol. [Internet]. [cited 2014 May 23];7:304–83. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/23890517. Gorden P, Lupsa BC, Chong AY, Lungu AO. Is there a human model for the Bmetabolic syndrome^ with a defined aetiology? Diabetologia [Internet]. 2010 [cited 2014 Jun 26];53:1534–6. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3499968&tool=pmcentrez&rendertype=abstract. Gorden P, Zadeh ES, Cochran E, Brown RJ. Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance. Endocr. Pract. [Internet]. [cited 2014 Mar 26];18:763–71. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3875336&tool=pmcentrez&rendertype=abstract. This case series describes the clinical approach to the treatment of syndromic insulin resistance and reports useful considerations when approaching these conditions with the choice of drug therapy. Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J. Clin. Endocrinol. Metab. [Internet]. 2002 [cited 2014 Jun 30];87:2395. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11994394. Moon H-S, Dalamaga M, Kim S-Y, Polyzos SA, Hamnvik O-P, Magkos F, et al. Leptin’s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr. Rev. [Internet]. 2013 [cited 2014 Mar 26];34:377–412. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23475416. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes [Internet]. 2005 [cited 2014 Jun 30];54:1994–2002. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/15983199. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr. Pract. [Internet]. [cited 2014 Jun 30];17:922– 32. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3498767&tool=pmcentrez&rendertype=abstract. Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes [Internet]. 2011 [cited 2014 Jun 30];60:1474–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3292320&tool=pmcentrez&rendertype=abstract. DePaoli A. Leptin in common obesity and associated disorders of metabolism. J. Endocrinol. [Internet]. 2014 [cited 2014 Jun 30]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24973357. Mantzoros CS. Leptin in relation to the lipodystrophy-associated metabolic syndrome. Diabetes Metab. J. [Internet]. 2012 [cited 2014 Mar 26];36:181–9. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3380121&tool= pmcentrez&rendertype=abstract. Hadigan C, Rabe J, Grinspoon S. Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance. J. Clin. Endocrinol. Metab. [Internet]. 2002 [cited 2014 Jul 2];87:4611–5. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/12364443.
12 75.
76.
77.
78.
79.
Curr Diab Rep (2015) 15:12
Page 10 of 10 Kohli R, Shevitz A, Gorbach S, Wanke C. A randomized placebocontrolled trial of metformin for the treatment of HIV lipodystrophy. HIV Med. [Internet]. 2007 [cited 2014 Jul 2];8:420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17760733. Chirico V, Ferraù V, Loddo I, Briuglia S, Amorini M, Salpietro V, et al. LMNA gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response. Diabetes Metab. [Internet]. 2014 [cited 2014 Mar 26]; Available from: http://www. ncbi.nlm.nih.gov/pubmed/24485160. Eldor R, DeFronzo RA, Abdul-Ghani M. In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care [Internet]. 2013 [cited 2014 Jul 2];36 Suppl 2:S162–74. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/23882042. Collet-Gaudillat C, Billon-Bancel A, Beressi J-P. Long-term improvement of metabolic control with pioglitazone in a woman with diabetes mellitus related to Dunnigan syndrome: a case report. Diabetes Metab. [Internet]. 2009 [cited 2014 Jun 4];35: 151–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 19249234. Raboud JM, Diong C, Carr A, Grinspoon S, Mulligan K, Sutinen J, et al. A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV Clin. Trials [Internet]. [cited 2014 Jul 3];11:39–50. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3733492&tool=pmcentrez&rendertype=abstract.
80.
Sutinen J. The effects of thiazolidinediones on metabolic complications and lipodystrophy in HIV-infected patients. PPAR Res. [Internet]. 2009 [cited 2014 Jul 2];2009:373524. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 2593088&tool=pmcentrez&rendertype=abstract. 81. Moreau F, Boullu-Sanchis S, Vigouroux C, Lucescu C, Lascols O, Sapin R, et al. Efficacy of pioglitazone in familial partial lipodystrophy of the Dunnigan type: a case report. Diabetes Metab. [Internet]. 2007 [cited 2014 Jun 4];33:385– 9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17936664. 82. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell [Internet]. 2012 [cited 2014 Jun 3];148:556–67. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3273727&tool=pmcentrez&rendertype=abstract. 83. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. [Internet]. 2013 [cited 2014 May 23];18:333–40. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/24011069. 84. Villarroya F, Domingo P, Giralt M. Lipodystrophy in HIV 1infected patients: lessons for obesity research. Int. J. Obes. (Lond). [Internet]. 2007 [cited 2014 Jun 9];31:1763–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17653062.
OTHER FORMS OF DIABETES (R BONADONNA, SECTION EDITOR)
Lipodystrophic Diabetes Mellitus: a Lesson for Other Forms of Diabetes? Romina Ficarella & Luigi Laviola & Francesco Giorgino
# Springer Science+Business Media New York 2015
Abstract Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes.
Keywords Lipodystrophy . Adipose tissue . Diabetes mellitus . Insulin resistance . Adipogenesis
This article is part of the Topical Collection on Other Forms of Diabetes R. Ficarella : L. Laviola : F. Giorgino (*) Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Giulio Cesare, n. 11, 70124 Bari, Italy e-mail: [email protected] R. Ficarella e-mail: [email protected] L. Laviola e-mail: [email protected]
Introduction Lipodystrophies include a heterogeneous group of disorders characterized by loss of adipose tissue (AT) in the subcutaneous compartment and several metabolic abnormalities associated with insulin resistance [1]. Although the definition of lipodystrophy is a Bwork in progress,^ as suggested by Rother and Brown [2••], the conventional classification of lipodystrophy, based on the topography of fat loss (general or partial) and on the inheritance (congenital or acquired), identifies four different subtypes: congenital generalized lipodystrophy, acquired generalized lipodystrophy, familial partial lipodystrophy (FPL), and acquired partial lipodystrophy (APL). In addition to the main characteristics of fat loss, these disorders are frequently characterized by hypertriglyceridemia, steatohepatitis, acanthosis nigricans, ovarian hyperandrogenism, and type 2 diabetes mellitus [1]. Multiple metabolic abnormalities, including insulin resistance, increased levels of free fatty acids and triglycerides, ectopic fat in skeletal muscle and hepatocytes, and abnormal secretion of adipokines, are typically observed in lipodystrophic patients but are also common in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) [3]. It is interesting to note that the consequences of lipoatrophy are remarkably similar to those of excessive fat accumulation, as observed in human obesity [4••]. Indeed, alterations in AT development and/or function due to mutations in genes involved in adipogenesis, lipid storage within the fat cell, or lipid droplet formation and turnover may cause severe metabolic consequences [5]. Even though the loss of fat per se may represent the primary cause of these metabolic changes, mitochondrial dysfunction [6], enhanced oxidative stress, and inflammation have been shown to contribute to the pathophysiology of the lipodystrophic phenotypes. In this review, we describe the Bmetabolic lipodystrophies^ as a disease model shedding light on specific pathophysiological
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mechanisms that can be informative for better understanding of more common metabolic diseases in humans, including visceral obesity, MS, and T2DM, potentially highlighting the basis for novel-integrated clinical approaches and therapies.
Classification of Lipodystrophies Lipodystrophies are generally diagnosed on the basis of the topography of fat loss (general or partial) and on the potential inheritance (congenital or acquired). Therefore, congenital generalized lipodystrophy (CGL), acquired generalized lipodystrophy (AGL), FPL, and APL represent the four main groups of disorders [1]. Patients with AGL—also designed as Lawrence syndrome and typically associated with autoantibodies against AT and other autoimmune diseases [7, 8]—develop progressive fat loss beginning in childhood or adolescence, with the initial involvement of the face and upper extremities. APL or Barraquer-Simons syndrome, of unknown etiology, is characterized by a gradual loss of subcutaneous fat progressing in a cephalocaudal direction with variable lower limit, with or without increased fat accumulation in the lower body [9]. A relatively frequent form of acquired lipodystrophy is induced by a highly active antiretroviral treatment (HAART) in HIV subjects, in which a severe lipoatrophy of subcutaneous AT associated with abdominal fat accumulation, severe dyslipidemia, insulin resistance, impaired glucose tolerance, and type 2 diabetes occur [10, 11]. Two main types of antiretroviral drugs are involved: nucleoside reverse transcriptase inhibitor (NRTI) analogues, which inhibit mitochondrial DNA polymerase-γ, the enzyme necessary for the replication of mitochondrial DNA [12] thereby inducing mitochondrial dysfunction, and HIV protease inhibitors (PIs). Some PIs also inhibit ZMPSTE24, the enzyme responsible for the removal of the farnesylated tail of prelamin A, leading to precursor accumulation inside the cells and impaired organization of the nuclear membrane [13], as also occurs in homozygous mutations in the gene encoding the ZMPSTE24 (as reported below). CGL, named Berardinelli-Seip congenital lipodystrophy (BSCL), is characterized by severe insulin resistance and the complete absence of AT starting from birth or early infancy. Mutations in proteins involved in adipocyte differentiation (seipin, BSCL2/BSCL2 [14]), FA uptake by adipocytes (caveolin-1, CAV1/BSCL3 [15]; DNA polymerase I and transcript release factor, PTRF/BSCL4 [16]), or triglyceride synthesis (1-acylglycerol-3-phosphate-O-acyltransferase 2, AGPAT2/ BSCL1 [17]) lead to a generalized lack of AT [18]. Mutations in other genes have been associated with generalized lipodystrophy: heterozygous mutations of LMNA, the gene encoding for A-type lamins, and homozygous mutations
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in the gene encoding the ZMPSTE24 (zinc metalloproteinase STE24 homolog) protease, which cleaves prelamin A into mature lamin A [1]. These two genes are respectively causative of the Hutchinson-Gilford progeria [19] and other progeroid syndromes [20], such as type B mandibuloacral dysplasia (MAD) [21, 18]. In FPLs, the clinical phenotype appears after puberty and the causative genes are peroxisome proliferator-activated receptor gamma (PPARγ) [22] and lamin A/C [23], encoding for nuclear proteins, or genes involved in insulin signaling, such as Akt2 [24], or regulators of the formation, trafficking, or maintenance of lipid droplets, including CIDEC [25] and perilipin [26]. Impaired AT Development and Function and Lipodystrophies In the last 15 years, novel mutations have been found to be responsible for lipodystrophic syndromes, bearing new light on the relationship between AT function and glucose and lipid metabolism [4••]. The lipodystrophy-causing genes include PPARγ, a key transcription factor for adipocyte differentiation; perilipin, involved in the regulation of lipolysis at the lipid droplet (LD) site; CIDEC, involved in the regulation of LD structure; the serine-threonine kinase Akt2; AGPAT2, which participates to triglyceride and glycerophospholipid synthesis; seipin, involved in LD formation; and caveolin-1, a structural protein of caveolae and LD. All of these genes are critical for the maturation of preadipocytes and/or the maintenance of the mature adipocyte phenotype, enlightening the leading role of AT for global metabolic homeostasis [4••]. Experimental mouse models, such as A-ZIP/F-1 fatless mice [27] and Agpat2-null lipodystrophic mice [28], show impaired glucose metabolism and insulin resistance. Moreover, after transplantation of normal subcutaneous AT into A-ZIP/F-1 fatless mice, the ectopic fat deposition was found to be reduced, with an improvement of insulin-mediated glucose uptake [27]. These results support the hypothesis that impaired AT development and/or function may result in metabolic abnormalities, which are commonly observed in T2DM and MS. The genetic lipodystrophies may thus serve as a model of the essential role of AT in the regulation of glucose and energy homeostasis. The contribution of relevant genes controlling AT differentiation and insulin signaling in the pathogenesis of human lipodystrophies has been widely addressed in recent focused reviews [4••, 18, 29–31]. More recently, other genetic lipodystrophies have been described, due to mutations which underline novel key steps in AT development and function, as outlined below. c-fos Knebel et al. reported a de novo homozygous point mutation (c.–439, T→A) in the c-fos promoter in a patient with CGL and insulin resistance. Fibroblasts isolated from the
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patient revealed a reduction of basal and inducible c-fos transcriptional activity, essential to initiate adipocyte differentiation, likely resulting in CGL [32]. p85α Chudasama et al. revealed a new element of the complex mechanism leading to partial lipodystrophy by identifying the regulatory subunit of PI3K, p85α, which is encoded by PIK3R1, as a genetic cause of the SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Rieger anomaly, and teething delay), also displaying partial lipodystrophy. PIK3R1 is a central component of the PI3K signaling pathway regulating cell metabolism and proliferation. Using a whole-exome sequencing approach, the authors identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two distinct families with partial lipodystrophy. This mutation prevents the association of p85α with IRS-1 and thus results in reduced Akt activation and insulin signaling in fibroblasts from the affected individuals [33], providing a link between the impaired insulin signaling and development of altered adipogenesis and the lipodystrophy syndrome. Phosphate Cytidylyltransferase 1 Alpha Payne et al. identified two unrelated patients with biallelic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in the Kennedy pathway of phospholipid biosynthesis [34]. The mutations result in a marked reduction in PCYT1A expression and in the synthesis of phosphatidylcholine, the major glycerophospholipid in eukaryotic cells and an essential component in all cellular membranes. The clinical phenotype includes lipodystrophy, severe fatty liver, low HDL cholesterol levels, marked insulin resistance, and diabetes, providing evidence for an essential role for PCYT1A-generated phosphatidylcholine in insulin action and in the regulation of white AT physiology [35]. Additionally, the pathophysiology of this specific lipodystrophy suggests that plasma membrane flexibility, determined by phospholipid composition, is important for the trafficking of both insulin-independent and insulindependent glucose transporters (GLUTs) and the effectiveness of glucose transport [36], providing an additional common pathogenic mechanism between lipodystrophy and impaired glucose metabolism. WRN (DNA helicase) Donadille et al. reported the cases of two women investigated for partial lipodystrophy (predominant fat accumulation in the trunk and reduced AT in the lower limbs) and severe insulin resistance, which revealed Werner’s syndrome due to homozygous or compound heterozygous, non-sense or frameshift mutations in the WRN gene, encoding a RecQ DNA helicase/ exonuclease involved in DNA replication and repair [37]. Bearing in mind that high glucose levels have been
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shown to induce oxidative DNA damage in diabetes, DNA replication and/or repair can be considered as a key metabolic target, potentially involved in the pathogenesis of more common metabolic diseases. Moreover, the role of insulin and glucose in modulating the expression of the DNA repair machinery is well established [38], supporting the hypothesis that impaired insulin action may be associated with deficient DNA repair function. Relevant to this concept, lymphocytes from diabetic patients displayed higher susceptibility to DNA damage when exposed to hydrogen peroxide or doxorubicin as well as decreased efficiency in repairing DNA injury [39]. Mandibular Hypoplasia, Deafness, and Progeroid Syndrome Progressive loss of subcutaneous AT, with concomitant severe insulin resistance, is a major feature of the recently described mandibular hypoplasia, deafness, and progeroid (MDP) syndrome [40]. The most prominent phenotype is the lack of subcutaneous AT which is first noted in early childhood, in contrast with the marked increase in visceral AT, and the clinical and biochemical evidence of insulin resistance despite BMI values G) in exon 9 of LMNA gene [76]. Thiazolidinediones The PPARγ agonist TZDs are potent insulin sensitizers that activate PPARγ, the master regulator of adipocyte differentiation, resulting in enhanced adipogenesis and adiponectin production, enhanced insulin secretion, and improved glucose tolerance [77], thus representing optimal candidates for AT dysfunction and diabetes in lipodystrophic patients. TZDs have been shown to increase subcutaneous fat in patients with lipodystrophy [78] and HIV-associated lipodystrophy [79, 80], by promoting adipocyte differentiation from AT progenitor cells. Specifically, therapy with pioglitazone has been shown to address multiple metabolic abnormalities associated with lipodystrophy, including increased adiponectin, improved lipid profiles and endothelial function, and amelioration of insulin resistance [81]. Fibroblast Growth Factor 21 Fibroblast growth factor 21 (FGF21), a circulating hepatokine, is also able to regulate the activity of PPARγ. Moreover, FGF21-knockout (KO) mice present with mild lipodystrophy, defects in PPARγ signaling, decreased body fat, and attenuation of PPARγdependent gene expression and are refractory to the beneficial
insulin-sensitizing effects of the PPARγ agonist rosiglitazone [82]. Adding recombinant FGF21 in the differentiation medium of preadipocytes derived from FGF21-KO mice resulted in effective restoration of gene expression of PPARγ, FA binding protein (aP2), and FA synthase (Fasn) and of lipid accumulation [82]. Although additional studies will be required to determine the relevance of FGF21 expression in human white AT in both physiologic and pharmacological contexts, these results suggest that FGF21 may contribute to the antidiabetic response to TZDs through PPARγ-dependent mechanisms, by increasing the number of small, metabolically active adipocytes and by raising circulating adiponectin levels [82]. LY2405319, a variant of FGF21, was recently tested in a randomized, placebo-controlled, double-blind proof-ofconcept trial in patients with obesity and T2DM. LY2405319 treatment resulted in significant improvements in dyslipidemia, body weight, fasting insulin, and adiponectin levels, suggesting that FGF21-based therapies may be effective for the treatment of selected metabolic disorders [83].
Conclusions Lipodystrophies are rare diseases, in which various degrees of AT loss are associated with severe lipid and glucose abnormalities, resulting into impairments of glucose tolerance or overt diabetes with a negative impact on the cardiovascular system and hepatic metabolism leading to related complications. The genetic bases of human lipodystrophies have been recently deciphered, highlighting the functional role of new proteins. Clinical whole-exome sequencing and murine models studies have greatly contributed to dissect the genetic complexities of lipodystrophies and their related metabolic
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features, largely shared by more common forms of diabetes. Most of the proteins or functions affected by mutations or antiretroviral therapies result in impaired adipogenesis and fat distribution as well as in reduced insulin sensitivity, triglyceride storage, and formation of the lipid droplet in adipocytes, revealing novel aspects of AT biology with potential impact on both diabetes research and the definition of novel treatments and/or prevention strategies. Villarroya et al. in 2007 [84] already described lipodystrophies as a lesson for obesity, emphasizing a common pathogenesis between these two metabolic disorders (Fig. 1). If we consider the AT expandability/ lipotoxicity hypothesis as the Bcommon soil^ for lipodystrophies and T2DM, understanding the pathogenesis and treatment of lipodystrophies may help to better address the abnormalities in lipid metabolism and adipocyte function underlying more common forms of diabetes.
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Conflict of Interest Romina Ficarella, Luigi Laviola, and Francesco Giorgino declare that they have no conflict of interest. 10. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. 11.
References 12.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Strickland LR, Guo F, Lok K, Garvey WT. Type 2 diabetes with partial lipodystrophy of the limbs: a new lipodystrophy phenotype. Diabetes Care [Internet]. 2013 [cited 2014 Mar 26];36:2247–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23423695. 2.•• Rother KI, Brown RJ. Novel forms of lipodystrophy: why should we care? Diabetes Care [Internet]. 2013 [cited 2014 Mar 26];36: 2142–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 23881965. This commentary highlights the heterogeneity of lipodystrophies, focusing on the need for a better nosographic definition, the relationship with fat accumulation and obesity, the metabolic impact, and the therapeutic approaches involving the use of leptin. 3. Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature [Internet]. 2006 [cited 2014 Mar 19];444:881–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167477. 4.•• Vatier C, Bidault G, Briand N, Guénantin A-C, Teyssières L, Lascols O, et al. What the genetics of lipodystrophy can teach us about insulin resistance and diabetes. Curr. Diab. Rep. [Internet]. 2013 [cited 2014 Mar 26];13:757–67. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24026869. This review article describes the genetics of lipodystrophic syndromes and addresses the mechanisms by which impaired adipogenesis and adipocyte lipid storage result in systemic metabolic and endocrine abnormalities.
13.
1.
14.
15.
16.
17.
18.
Araújo-Vilar D, Lattanzi G, González-Méndez B, Costa-Freitas AT, Prieto D, Columbaro M, et al. Site-dependent differences in both prelamin A and adipogenic genes in subcutaneous adipose tissue of patients with type 2 familial partial lipodystrophy. J. Med. Genet. [Internet]. 2009 [cited 2014 Mar 27];46:40–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18805829. Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, et al. Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy. J. Clin. Endocrinol. Metab. [Internet]. 2012 [cited 2014 Mar 26];97:E438–42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3380089&tool=pmcentrez&rendertype=abstract. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). [Internet]. 2003 [cited 2014 Mar 26];82:129–46. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/12640189. Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, et al. Complement abnormalities in acquired lipodystrophy revisited. J. Clin. Endocrinol. Metab. [Internet]. 2009 [cited 2014 Jun 23];94:10–6. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18854390. Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. [Internet]. 2011 [cited 2014 Mar 20];96:3313–25. Available from: http://www.ncbi. nlm.nih.gov/pubmed/21865368. Villarroya F, Domingo P, Giralt M. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Trends Pharmacol. Sci. [Internet]. 2005 [cited 2014 Apr 3];26:88–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15681026. Kalra S, Agrawal N. Diabetes and HIV: current understanding and future perspectives. Curr. Diab. Rep. [Internet]. 2013 [cited 2014 Mar 26];13:419–27. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/23446780. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion [Internet]. 2004 [cited 2014 Oct 21];4:111–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16120376. Goulbourne CN, Vaux DJ. HIV protease inhibitors inhibit FACE1/ ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy? Biochem. Soc. Trans. [Internet]. 2010 [cited 2014 Oct 21];38:292–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20074077. Magré J, Delépine M, Khallouf E, Gedde-Dahl T, Van Maldergem L, Sobel E, et al. Identification of the gene altered in BerardinelliSeip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28:365–70. Kim CA, Delépine M, Boutet E, El Mourabit H, Le Lay S, Meier M, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93:1129–34. Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009:2623–33. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31: 21–3. Vigouroux C, Caron-Debarle M, Le Dour C, Magré J, Capeau J. Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Int. J. Biochem. Cell Biol. [Internet]. 2011 [cited 2014 Jun 10];43:862–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21392585.
12 19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29. 30.
31.
32.
33.
34.
Page 8 of 10 Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–8. Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D’Apice MR, et al. Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab. 2009;94:4971–83. Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12:1995–2001. Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, et al. Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3. ST – Dominant negative mutations in human. Available from: :// 000084482000034. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109–12. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8. Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 2009;1:280–7. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N. Engl. J. Med. [Internet]. 2011 [cited 2014 Mar 21];364:740–8. Available from: http://www.pubmedcentral.nih. g o v / a r t i c l e r e n d e r. f c g i ? a r t i d = 3 7 7 3 9 1 6 & t o o l = pmcentrez&rendertype=abstract. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J. Biol. Chem. [Internet]. 2000 [cited 2014 Jun 11];275:8456–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10722680. Agarwal AK, Sukumaran S, Cortés VA, Tunison K, Mizrachi D, Sankella S, et al. Human 1-acylglycerol-3-phosphate Oacyltransferase isoforms 1 and 2: biochemical characterization and inability to rescue hepatic steatosis in Agpat2(−/−) gene lipodystrophic mice. J. Biol. Chem. [Internet]. 2011 [cited 2014 Ju n 11 ] ; 28 6: 37 676 –9 1. Avai l a b l e fr o m : http:/ /www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3199511&tool= pmcentrez&rendertype=abstract. Jeninga EH, Kalkhoven E. Central players in inherited lipodystrophies. Trends Endocrinol Metab. 2010;21:581–8. Rochford JJ. Molecular mechanisms controlling human adipose tissue development: insights from monogenic lipodystrophies. Expert Rev Mol Med. 2010;12:e24. Huang-Doran I, Sleigh A, Rochford JJ, O’Rahilly S, Savage DB. Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol. 2010;207:245–55. Knebel B, Kotzka J, Lehr S, Hartwig S, Avci H, Jacob S, et al. A mutation in the c-fos gene associated with congenital generalized lipodystrophy. Orphanet J. Rare Dis. [Internet]. 2013 [cited 2014 Jun 11];8:119. Available from: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3750569&tool=pmcentrez&rendertype= abstract. Chudasama KK, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, et al. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am. J. Hum. Genet. [Internet]. 2013 [cited 2014 Mar 26];93:150–7. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3710758&tool=pmcentrez&rendertype=abstract. Gibellini F, Smith TK. The Kennedy pathway—de novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB
Curr Diab Rep (2015) 15:12 Life [Internet]. 2010 [cited 2014 Jul 21];62:414–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20503434. 35. Payne F, Lim K, Girousse A, Brown RJ, Kory N, Robbins A, et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc. Natl. Acad. Sci. [Internet]. 2014 [cited 2014 Jun 4]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24889630. 36. Weijers RNM. Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus. Curr. Diabetes Rev. [Internet]. 2012 [cited 2014 May 30];8:390–400. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3474953&tool=pmcentrez&rendertype=abstract. 37. Donadille B, D’Anella P, Auclair M, Uhrhammer N, Sorel M, Grigorescu R, et al. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet J. Rare Dis. [Internet]. 2013 [cited 2014 Jun 11];8:106. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3720184&tool=pmcentrez&rendertype=abstract. 38. Merkel P, Khoury N, Bertolotto C, Perfetti R. Insulin and glucose regulate the expression of the DNA repair enzyme XPD. Mol Cell Endocrinol. 2003;201:75–85. Available from: http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt= Citation&list_uids=12706296. 39. Blasiak J, Arabski M, Krupa R, Wozniak K, Zadrozny M, Kasznicki J, et al. DNA damage and repair in type 2 diabetes mellitus. Mutat Res. 2004;554:297–304. 40. Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, et al. A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism. J Clin Endocrinol Metab. 2010; E192–E197. 41. Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat. Genet. [Internet]. 2013 [cited 2014 Jun 11];45:947–50. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3785143&tool=pmcentrez&rendertype=abstract. 42. Miranda DA, Kim J-H, Nguyen LN, Cheng W, Tan BC, Goh VJ, et al. Fat storage-inducing transmembrane protein 2 is required for normal fat storage in adipose tissue. J. Biol. Chem. [Internet]. 2014 [cited 2014 May 28];289:9560–72. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24519944. 43. Frontini A, Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 2010;253–6. 44. Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature. 2014;510:76–83. Available from: http://www.ncbi.nlm. nih.gov/pubmed/24899307 45. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–5. 46. Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–76. 47. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24100998. 48. Guerra C, Navarro P, Valverde AM, Arribas M, Brüning J, Kozak LP, et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest. 2001;108:1205–13. 49. Van de Woestijne AP, Monajemi H, Kalkhoven E, Visseren FLJ. Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management. Obes. Rev. [Internet]. 2011 [cited 2014 Jun 25];12:829–40. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/21749607.
Curr Diab Rep (2015) 15:12 50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes [Internet]. 2003 [cited 2014 Jun 25];52:2461–74. Available from: http://www.ncbi. nlm.nih.gov/pubmed/14514628. Borén J, Taskinen M-R, Olofsson S-O, Levin M. Ectopic lipid storage and insulin resistance: a harmful relationship. J. Intern. Med. [Internet]. 2013 [cited 2014 Jun 20];274:25–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23551521. Giralt M, Díaz-Delfín J, Gallego-Escuredo JM, Villarroya J, Domingo P, Villarroya F. Lipotoxicity on the basis of metabolic syndrome and lipodystrophy in HIV-1-infected patients under antiretroviral treatment. Curr. Pharm. Des. [Internet]. 2010 [cited 2014 Jun 12];16:3371–8. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/20687888. Vigouroux C, Maachi M, Nguyên T-H, Coussieu C, Gharakhanian S, Funahashi T, et al. Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS. 2003;17:1503–11. Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. Int. J. Obes. (Lond). [Internet]. 2010 [cited 2014 Jun 9];34:949–59. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20065965. Patti M-E, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. [Internet]. 2010 [cited 2014 Mar 31];31: 364–95. Available from: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3365846&tool=pmcentrez&rendertype= abstract. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. [Internet]. 2008 [cited 2014 Mar 31];7:45–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18177724. Villarroya J, Giralt M, Villarroya F. Mitochondrial DNA: an upand-coming actor in white adipose tissue pathophysiology. Obesity (Silver Spring). [Internet]. 2009 [cited 2014 Mar 21];17: 1814–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 19461585. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol. Cell. Biol. [Internet]. 2003 [cited 2014 Apr 1];23:1085–94. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=140688&tool=pmcentrez&rendertype=abstract. Koh EH, Park J-Y, Park H-S, Jeon MJ, Ryu JW, Kim M, et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes [Internet]. 2007 [cited 2014 Apr 3];56: 2973–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17827403. Shi X, Burkart A, Nicoloro SM, Czech MP, Straubhaar J, Corvera S. Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells. J. Biol. Chem. [Internet]. 2008 [cited 2014 Mar 27];283:30658–67. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2576555&tool=pmcentrez&rendertype=abstract. Domingo P, Gutierrez MDM, Gallego-Escuredo JM, Torres F, Mateo GM, Villarroya J, et al. Effects of switching from stavudine to raltegravir on subcutaneous adipose tissue in HIV-infected patients with HIV/HAART-associated lipodystrophy syndrome (HALS). A clinical and molecular study. PLoS One [Internet]. 2014 [cited 2014 Mar 26];9:e89088. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3935839&tool= pmcentrez&rendertype=abstract. Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, et al. Cardiovascular pathology in Hutchinson-Gilford progeria:
Page 9 of 10 12
63.
64.
65.
66.•
67.
68.
69.
70.
71.
72.
73.
74.
correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol. 2010;30:2301–9. Bidault G, Garcia M, Vantyghem M-C, Ducluzeau P-H, Morichon R, Thiyagarajah K, et al. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler. Thromb. Vasc. Biol. [Internet]. 2013 [cited 2014 Mar 26];33:2162–71. Available from: http://www.ncbi. nlm.nih.gov/pubmed/23846499. Bays HE, Toth PP, Kris-Etherton PM, Abate N, Aronne LJ, Brown WV, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J. Clin. Lipidol. [Internet]. [cited 2014 May 23];7:304–83. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/23890517. Gorden P, Lupsa BC, Chong AY, Lungu AO. Is there a human model for the Bmetabolic syndrome^ with a defined aetiology? Diabetologia [Internet]. 2010 [cited 2014 Jun 26];53:1534–6. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3499968&tool=pmcentrez&rendertype=abstract. Gorden P, Zadeh ES, Cochran E, Brown RJ. Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance. Endocr. Pract. [Internet]. [cited 2014 Mar 26];18:763–71. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3875336&tool=pmcentrez&rendertype=abstract. This case series describes the clinical approach to the treatment of syndromic insulin resistance and reports useful considerations when approaching these conditions with the choice of drug therapy. Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J. Clin. Endocrinol. Metab. [Internet]. 2002 [cited 2014 Jun 30];87:2395. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11994394. Moon H-S, Dalamaga M, Kim S-Y, Polyzos SA, Hamnvik O-P, Magkos F, et al. Leptin’s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr. Rev. [Internet]. 2013 [cited 2014 Mar 26];34:377–412. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23475416. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes [Internet]. 2005 [cited 2014 Jun 30];54:1994–2002. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/15983199. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr. Pract. [Internet]. [cited 2014 Jun 30];17:922– 32. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3498767&tool=pmcentrez&rendertype=abstract. Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes [Internet]. 2011 [cited 2014 Jun 30];60:1474–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3292320&tool=pmcentrez&rendertype=abstract. DePaoli A. Leptin in common obesity and associated disorders of metabolism. J. Endocrinol. [Internet]. 2014 [cited 2014 Jun 30]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24973357. Mantzoros CS. Leptin in relation to the lipodystrophy-associated metabolic syndrome. Diabetes Metab. J. [Internet]. 2012 [cited 2014 Mar 26];36:181–9. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3380121&tool= pmcentrez&rendertype=abstract. Hadigan C, Rabe J, Grinspoon S. Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance. J. Clin. Endocrinol. Metab. [Internet]. 2002 [cited 2014 Jul 2];87:4611–5. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/12364443.
12 75.
76.
77.
78.
79.
Curr Diab Rep (2015) 15:12
Page 10 of 10 Kohli R, Shevitz A, Gorbach S, Wanke C. A randomized placebocontrolled trial of metformin for the treatment of HIV lipodystrophy. HIV Med. [Internet]. 2007 [cited 2014 Jul 2];8:420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17760733. Chirico V, Ferraù V, Loddo I, Briuglia S, Amorini M, Salpietro V, et al. LMNA gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response. Diabetes Metab. [Internet]. 2014 [cited 2014 Mar 26]; Available from: http://www. ncbi.nlm.nih.gov/pubmed/24485160. Eldor R, DeFronzo RA, Abdul-Ghani M. In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care [Internet]. 2013 [cited 2014 Jul 2];36 Suppl 2:S162–74. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/23882042. Collet-Gaudillat C, Billon-Bancel A, Beressi J-P. Long-term improvement of metabolic control with pioglitazone in a woman with diabetes mellitus related to Dunnigan syndrome: a case report. Diabetes Metab. [Internet]. 2009 [cited 2014 Jun 4];35: 151–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 19249234. Raboud JM, Diong C, Carr A, Grinspoon S, Mulligan K, Sutinen J, et al. A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV Clin. Trials [Internet]. [cited 2014 Jul 3];11:39–50. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3733492&tool=pmcentrez&rendertype=abstract.
80.
Sutinen J. The effects of thiazolidinediones on metabolic complications and lipodystrophy in HIV-infected patients. PPAR Res. [Internet]. 2009 [cited 2014 Jul 2];2009:373524. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 2593088&tool=pmcentrez&rendertype=abstract. 81. Moreau F, Boullu-Sanchis S, Vigouroux C, Lucescu C, Lascols O, Sapin R, et al. Efficacy of pioglitazone in familial partial lipodystrophy of the Dunnigan type: a case report. Diabetes Metab. [Internet]. 2007 [cited 2014 Jun 4];33:385– 9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17936664. 82. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell [Internet]. 2012 [cited 2014 Jun 3];148:556–67. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3273727&tool=pmcentrez&rendertype=abstract. 83. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. [Internet]. 2013 [cited 2014 May 23];18:333–40. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/24011069. 84. Villarroya F, Domingo P, Giralt M. Lipodystrophy in HIV 1infected patients: lessons for obesity research. Int. J. Obes. (Lond). [Internet]. 2007 [cited 2014 Jun 9];31:1763–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17653062.
